There are nine inherited neurodegenerative disorders caused by the expansion of a polyglutamine (polyQ) domain in proteins associated with various diseases, including Huntington's disease (HD) and several spinocerebellar ataxia (SCA) disorders. Although all polyQ disease proteins are widely expressed in the brain and body, they selectively kill neurons in distinct brain regions depending on the polyQ disease involved. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration is critical to the development of effective therapeutic strategies for treating these polyQ diseases. It is now clear that protein context modulates the toxicity of polyQ expansion and determines the selective neurodegeneration seen in polyQ diseases; however, the exact mechanism for this selective neurodegeneration remains unknown. It is apparent that before we can uncover this mechanism, we must first understand the function of the polyQ protein. In this application, we will focus on SCA17 to explore the issue of selective neurodegeneration in polyQ diseases. Spinocerebellar ataxia type 17 (SCA17) is caused by polyQ expansion in TBP, a TATA-box binding protein that is essential for gene transcription. Expansion of the polyQ domain in this important transcription factor also induces selective neurodegeneration reminiscent of HD and other polyQ diseases. As the function and structure of TBP are well characterized, SCA17 makes an excellent model for studying how polyQ expansion alters normal protein function and causes neurodegeneration. Our earlier studies have demonstrated that the expanded polyQ domain can alter the binding of TBP to DNA and transcriptional factors. In this application, we will focus on how mutant TBP with an expanded polyQ causes selective neurodegeneration in the brain. We hypothesize that the accumulation of toxic forms of mutant TBP may be different in affected neurons versus other types of cells and that this difference contributes to neuronal vulnerability. To test this hypothesis, we will use conditional SCA17 knock-in mice that express mutant TBP in selected types of cells at the endogenous level. Specifically, in Aim 1 we will examine the neurological phenotypes of conditional SCA17 knock-in mice that selectively express mutant TBP in different types of cells. In Aim 2 we will investigate whether different forms of mutant TBP accumulate differently in various types of cells. In Aim 3 we will study the effects of different forms of mutant TBP on nuclear transcription factors and related neuronal function. These studies will give us insight into the pathogenesis of SCA17 and the selective neurodegeneration seen in polyQ diseases.